The leukocyte common antigen-related protein tyrosine phosphatase receptorregulates regenerative neurite outgrowth in vivo

Drosophila and leech models of nervous system development demonstrate that protein tyrosine phosphatase (PTP) receptors regulate developmental neurite outgrowth. Whether PTP receptors regulate neurite outgrowth in adult syste ms or in regenerative states remains unknown. The leukocyte common antigen- related (LAR) receptor is known to be present in rodent dorsal root ganglio n (DRG) neurons; therefore, the well established model of postcrush sciatic nerve regeneration was used to test the hypothesis that LAR is required fo r neurite outgrowth in the adult mammalian nervous system. In uninjured sci atic nerves, no differences in nerve morphology and sensory function were d etected between wild-type and LAR-deficient littermate transgenic mice. Sci atic nerve crush resulted in increased LAR protein expression in DRG neuron s. In addition, nerve injury led to an increase in the proportion of LAR pr otein isoforms known to have increased binding affinity to neurite-promotin g laminin-nidogen complexes. Two weeks after nerve crush, morphological ana lysis of distal nerve segments in LAR-deficient transgenic mice demonstrate d significantly decreased densities of myelinated fibers, decreased axonal areas, and increased myelin/axon area ratios compared with littermate contr ols. Electron microscopy analysis revealed a significant twofold reduction in the density of regenerating unmyelinated fibers in LAR-/- nerves distal to the crush site. Sensory testing at the 2 week time point revealed a corr esponding 3 mm lag in the proximal-to-distal progression of functioning sen sory fibers along the distal nerve segment. These studies introduce PTP rec eptors as a major new gene family regulating regenerative neurite outgrowth in vivo in the adult mammalian system.